SCA28, a novel form of autosomal dominant cerebellar ataxia on chromosome 18p11.22–q11.2

Abstract

We describe a four-generation Italian family with a novel form of juvenile-onset, slowly progressive, autosomal dominant cerebellar ataxia. Eleven affected family members have been evaluated. The mean age at onset was 19.5 years with no evidence of anticipation. The first symptoms were invariably unbalanced standing and mild gait incoordination. Gaze-evoked nystagmus was prominent at onset, while patients with longer disease duration developed slow saccades, ophthalmoparesis and, often, ptosis. Deep tendon reflexes in lower limbs were increased in 80% of the cases. Genetic analysis excluded the presence of pathological repeat expansions in spinocerebellar ataxia (SCA) types 1-3, 6-8, 10, 12 and 17, and DRPLA genes. Linkage exclusion tests showed no evidence of association with other known SCA loci. A genome-wide screen analysis identified linkage with chromosome 18 markers. A maximum two-point limit of determination score of 4.20 was found for marker D18S53. Haplotype analysis refined a critical region of 7.9 Mb between markers D18S1418 and D18S1104. This new SCA locus on 18p11.22-q11.2 has been designated SCA28. Candidate genes within the critical interval are currently screened for mutations.

Analysis of segregation patterns in Machado–Joseph disease pedigrees

“…SCAs are considered rare disorders, as their prevalence has been estimated to be *3 in 100,000. As a member of the SCA group, MJD is considered the most common form of SCA worldwide (Cagnoli et al 2006). The Azores, a group of Portuguese Islands to where the first descriptions of MJD trace (Nakano et al 1972;Woods and Schaumburg 1972), remain the most important cluster of this disease.…”

Spectrum and prevalence of autosomal dominant spinocerebellar ataxia in Hokkaido, the northern island of Japan: a study of 113 Japanese families

“…To date, 29 different genetic loci have been reported to be responsible for ADCA (http://www.gene.ucl.ac.uk/cgi-bin/nomenclature): spinocerebellar ataxia type 1 (SCA1) on chromosome 6p22-p23 (Orr et al 1993); SCA2 on 12q23-q24.1 (Imbert et al 1996;Sanpei et al 1996); Machado-Joseph disease (MJD)/ SCA3 on 14q24.3-q32.1 (Kawaguchi et al 1994); SCA4 on 16q22.1 (Flanigan et al 1996); SCA5 on 11q13.2 (Ranum et al 1994); SCA6 on 19p13.1 (Zhuchenko et al 1997); SCA7 on 3p12-p13 (David et al 1997); SCA8 on 13p (Koob et al 1999); SCA10 on 22q13-qter. (Matsuura et al 2000); SCA11 on 15q14-q21.3 (Worth et al 1999); SCA12 on 5q31-33 (Holmes et al 1999);SCA13 on 19q13.3-q13.4 (Waters et al 2006); SCA14 on 19q13.42 Chen et al 2003;Yabe et al 2003); SCA15 on 3p24.2 (Gardner et al 2005); SCA16 on 8q23-q24.1 (Miyoshi et al 2001); SCA17 on 6q27 (Nakamura et al 2001); SCA18 on 7q22 (Brkanac et al 2002); SCA19 on 1p21-q21 (Verbeek et al 2002); SCA20 on 11p11.2-q13.3 (Knight et al 2004); SCA21 on 7p21.3-p15.1 (Vuillaume et al 2002); SCA22 on 1p21-q23 (Chung et al 2003); SCA23 on 20p13-p12 (Verbeek et al 2004); SCA24 on 1p26 (Swartz et al 2002); SCA25 on 2p21-p15 (Stevanin et al 2004); SCA26 on 19p13.3 (Yu et al 2005); SCA27 on 13q33.1 (Van Swieten et al 2003); SCA28 on 18p11.22-q11.2 (Cagnoli et al 2006); SCA 29 on 3p26 (Dudding et al 2004) and dentatorubral pallidoluysian atrophy (DRPLA) on 12p13.31 (Koide et al 1994;Nagafuchi et al 1994). Among these loci, causative genes have been further identified containing trinucleotide repeats (CAG) in S...…”

Effect of Trehalose on the Properties of Mutant γPKC, Which Causes Spinocerebellar Ataxia Type 14, in Neuronal Cell Lines and Cultured Purkinje Cells*

“…Autosomal dominant spinocerebellar ataxias (SCAs) 2 are a heterogeneous group of neurological disorders that are clinically characterized by various symptoms of cerebellar dysfunction, including progressive ataxia of gait and limbs, cerebellar dysarthria, and abnormal eye movement. SCAs are classified into at least 28 types according to the chromosomal location of the causal genes (1)(2)(3).…”

“…SCAs are classified into at least 28 types according to the chromosomal location of the causal genes (1)(2)(3). CAG trinucleotide repeat expansions in coding regions were the first types of mutations identified in SCAs (SCA1, -2, -3, -6, -7, and -17 and dentatorubral pallidoluysian atrophy), which are considered polyglutamine diseases (4,5).…”